Ever since their existence, there has been an everlasting arms race between viruses and their host cells. Host cells have developed numerous strategies to silence viral gene expression, whereas viruses always find ways to overcome these obstacles. Accordingly, viruses have evolved to take full advantage of existing cellular chromatin components to activate or repress its own genes when needed. In fact, host epigenetic modifications of the herpesviral genome chromatin play a key role in the transcriptional control of latent and lytic genes during a productive viral lifecycle. Kaposi's sarcoma-associated herpesvirus (KSHV) is a ubiquitous herpesvirus that establishes a life-long persistent infection in humans and is associated with Kaposi's sarcoma and several lymphoid malignancies. During latency, the KSHV genome persists as a multicopy circular DNA assembled into nucleosomal structures. While viral latency is characterized by restricted viral gene expression, reactivation induces the lytic replication program and the expression of viral genes in a defined sequential and temporal order. Our preliminary study demonstrates that (1) the latent and lytic chromatins of KSHV are associated with a distinctive pattern of activating and repressive histone modifications whose distribution changes upon reactivation in an organized manner in correlation with the temporally ordered expression of viral lytic genes. Furthermore, (2) the evolutionarily conserved Polycomb group proteins and histone deubiquitinases also play a critical role in the regulation of KSHV latency and reactivation by regulating the viral chromatin structure. Thus, the epigenetic program of KSHV is at the crux of restricting latent gene expression and the orderly expression of lytic genes. The goal of this study is to better understand how epigenetic modifications of the KSHV genome affect viral latency and lytic replication, to thereby contribute to the development of a persistent infection and subsequent pathogenic events in vivo. Based on our preliminary studies, we hypothesize that the proper epigenetic regulation of the KSHV genome is critical for viral persistency during latency and reactivation, and for pathogenesis in KSHV infected lesions. This proposal is highly innovative, utilizing well-established comprehensive genome-wide ChIP array, BAC genetics, and in vivo experimental conditions. PUBLIC HEALTH RELEVANCE: Kaposi sarcoma (KS) is the leading cause of cancer in patients with HIV infection. While there is a reduction in the incidence of KS among patients receiving HAART, an increasing concern is the development and spread of drug resistant HIV-1 strains, which in turn leads to reoccurrence of KS complication. Kaposi's sarcoma-associated herpesvirus (KSHV) is an etiological agent to induce KS tumors, pleural effusion lymphomas and multicentric Castleman's disease. We have recently developed a new primate model that significantly recapitulates the important aspects of the KSHV infection and pathogenesis of humans, thus providing a unique tool for understanding KSHV infection. The goal of this study is to better understand how epigenetic modifications of the KSHV genome affect viral latency and lytic replication, to thereby contribute to the development of a persistent infection and subsequent pathogenic events in vivo. The proposed study is highly innovative by utilizing the well-established in vitro and in vivo experimental conditions and a successful outcome should be a major discovery that significantly impacts the understanding of KSHV persistent and pathogenic infection.